1. Field of Invention
The current invention relates to microfluidic devices, and more particularly to microfluidic devices that include a droplet generator.
2. Discussion of Related Art
Thorough mixing is paramount for performing chemical or biochemical reactions to achieve high and repeatable yields. Rapid mixing improves desired reactions by avoiding side reactions caused by, for example, large excess of one reagent in uneven distribution. Speed of mixing may be particularly important in certain applications such as, for example, certain fast organic/inorganic syntheses or radiolabeling of imaging probes for positron emission tomography (PET) because of the short half-life time of the radioisotopes used.
Microfluidic chips typically manipulate fluid volumes in the range of nL (nanoliters) to μL (microliters). Mixing in these chips is challenging due to the absence of turbulence under most normal operating conditions due to low Reynold's number. As is well known in the art, the mixing rate is generally limited by diffusion. For example, if two streams enter a single channel at a Y-junction, the streams will flow side-by-side and, depending on flow rates and diffusion constants, a relatively long flow distance is needed before the streams are well-mixed by diffusion.
A vast range of mixing methods and chip designs have been reported in the literature (Nguyen, N-T, Wu, Z., Micromixers—a review, J. Micromech. Microeng. 15: R1-R16 2005; Hessel, V., Lowe, H., Schonfeld, F., Micromixers—a review on passive and active mixing principles, Chemical Engineering Science 60: 2479-2501, 2005). Passive and active means to “stretch and fold” the fluids to be mixed have been reported in which the diffusion distance is decreased and mixing by diffusion may occur more rapidly (Gunther, A., Jhunjhunwala, M., Thalmann, M., Schmidt, M. A., Jensen, K. F., Micromixing of miscible liquids in segmented gas-liquid flow, Langmuir 21(4): 1547-1555, 2005).
Droplet-based mixing may be the most efficient as measured in terms of time and on-chip space, in contrast to other forms of mixing that take much more time and on-chip space. One method of droplet-based mixing employs a continuous flow droplet-based approach (Gunther, A., Jhunjhunwala, M., Thalmann, M., Schmidt, M. A., Jensen, K. F., Micromixing of miscible liquids in segmented gas-liquid flow, Langmuir 21(4): 1547-1555 2005; Song, H., Chen, D. L., Ismagilov, R. F., Reactions in proplets in Microfluidic Channels, Angewandte Chemie 45: 7336-7356, 2006; Song, H., Bringer, M. R., Tice, J. D. Gerdts, C. J., Ismagilov, R. F., Experimental test of scaling of mixing by chaotic advection in droplets moving through microfluidic channels, Applied Physics Letters 83(22): 4664-4666, 2003; Song, H., Ismagilov, R. F., Millisecond kinetics on a microfluidic chip using nanoliters of reagents, J. Am. Chem. Soc. 125: 14613-14619, 2003). Droplets containing two or more reagents with desired ratios of volume are created by physical processes and flow along a microchannel. The flow process generates a chaotic mixing action within a droplet that may improve mixing length and time. For example, the Ismagilov group has observed sub-second mixing time in a dispersionless droplet mixing technology that they developed (Ismagilov, R. F., Experimental test of scaling of mixing by chaotic advection in droplets moving through microfluidic channels, Applied Physics Letters 83(22): 4664-4666, 2003; Song, H., Ismagilov, R. F., Millisecond kinetics on a microfluidic chip using nanoliters of reagents, J. Am. Chem. Soc. 125: 14613-14619, 2003). They found that the spatial distribution of liquids within a droplet is critical to the mixing efficiency in straight mixing channels. Specifically, a droplet that has end-to-end distribution mixes more efficiently than a droplet having a side-by-side distribution. The reason is that liquid flowing in a straight channel creates a recirculation within each half, side-by-side, in the droplet. A serpentine flow path may be needed for more efficient mixing of a droplet having a side-by-side distribution.
Although fast mixing may be achieved, the implementation is difficult for a number of applications, especially those using low volumes of at least one reagent. This is because it is hard to make the reagents that are being mixed arrive at the mixing junction exactly at the same time. Quite often, some droplets have to be discarded due to, for example, incorrect volume ratios. Incorrect ratios also can occur as droplet formation stabilizes in the first several minutes of operation, requiring the incorrectly formed droplets to be discarded. Furthermore, flow rates and other parameters must be laboriously tuned with care since operation depends on, for example, temperature, viscosity, type of solvents, number of reagents, desired volume ratios, etc. For example, Tice et al (Tice, J. D., Lyon, A. D., Ismagilov, R. F., Effects of viscosity on droplet formation and mixing in microfluidic channels, Analytica Chimica Acta 507: 73-77, 2004) observed viscosity to have an enormous impact on initial spatial distribution of reagents within each droplet, ranging from optimally good to the opposite for mixing in a straight channel. Variations in conditions over time can affect droplet uniformity. Generation of series of droplets having different sizes, volume ratios, etc. is especially difficult and many droplets must be discarded in the transition interval as operating parameters are altered.
In addition to the passive mixers that have been demonstrated in continuous flow microfluidic devices, active mixing has been demonstrated in integrated microfluidic chips. For example, the rotary mixer developed by Quake et al. (Chou, H-P, Unger, M. A., Quake, S. R. A microfabricated rotary pump, Biomedical Microdevices 3(4): 323-330, 2001; Hansen, C. L., Sommer, M. O. A., Quake, S. R., Systematic investigation of protein phase behavior with a microfluidic formulator, PNAS 101(40): 14431-14436, 2004) may be the most commonly used approach and has a simple fabrication process. The mixer, for example, may have one continuous closed path (e.g., a ring) around which fluids can be pumped. Due to extreme Taylor dispersion, the fluids become mixed after several cycles around the ring (Squires, T. M., Quake, S. R. Microfluidics: fluid physics on the nanoliter scale, Reviews of Modern Physics 77: 977-1026, 2005). The use of microvalves, in constrast to continuous flow microfluidic devices, can facilitate the manipulation of very small fluid volumes.
The rotary mixer and its variations, however, are not scalable designs. As the volume/length of the mixer increases, a longer time is required for circulating the fluids, and the effectiveness of pumping diminishes. For modest volumes (e.g., 1 μL), it can take several minutes to achieve thorough mixing. Furthermore, the rotary mixer and its variations are sensitive to the presence of bubbles, which may occur in a reaction resulting in the fluids being heated above the boiling point or the release of gas.
Therefore, there is a need for devices and methods for rapid and accurate mixing for integrated microfluidic devices.